I can just see little kids (5 - 6 yo) given this because it's sublingual, the doc pushing the dose to the maximum adult dose (10 mg bid), and the kid swallowing the drug once the tablet disintegrates.
Personally I think we're going to be seeing a lot of liver failure in kids.
Since PAH is already being reported with the other atypicals in kids I think this one will also be problematic. We just won't know how bad until someone like Dave Graham (Vioxx) fights FDA management to let the info out.
Look for it in about 5 years.
-- Salmon
July 30, 2009 3:34 PM
From the Kenilworth press release:
. . . .the FDA has approved Saphris® (asenapine) sublingual tablets for acute treatment of schizophrenia in adults and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. Saphris can be used as a first-line treatment and is the first psychotropic drug to receive initial approval for both of these indications simultaneously.
Saphris is expected to be available in the U.S. during the fourth quarter of 2009. . . .
Elevated Risk of Death in Eldery Patients: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5 percent compared to a rate of 2.6 percent in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis.
Cerebrovascular Adverse Events: There was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis.Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with administration of antipsychotic drugs, including SAPHRIS. NMS can cause hyperpyrexia, muscle rigidity, altered mental status, irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems.
Tardive Dyskinesia (TD): The risk of developing TD and the potential for it to become irreversible may increase as the duration of treatment and the total cumulative dose increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing should be consistent with the need to minimize TD. If signs and symptoms appear, discontinuation should be considered. . . .
I think this is why the "labeling discussions" (i.e., "Black Box" warnings) were so-long in the baking, between Schering-Plough's lawyers, on the one hand, and the FDA staffers, on the other.
Upon a full, and fair, review of the available scientific data, Saphris (asenapine) is appropriate for only a very small sub-set of the severely mentally-ill people that might have once been considered candidates for it. I fear Salmon is right -- this will soon be prescribed by doctors -- overly influenced by Schering-Plough detailing efforts (the newly-hired whiz-kids are hitting the pavement as I type this), off-label, even -- and we will see bad CV and hepatox results in the post-approval studies, about five years on. Unfortunate. Truly. The whole system is sorta' broken.Unless FDA mandates that Schering-Plough/New Merck track all the severely mentally-ill patients (many in state-run institutions) actually prescribed asenapine, we may never know how many will be harmed, rather than helped, by a too-wide application of this very powerful chemical compound -- with a very-severe side-effect profile. Side effects that plainly include deaths, here.
5 comments:
Unforunately, the bold AEs that you put forward are class effects and include class effects known among the older classical antipsychtics. So:
Increased risk of death in elderly. They all have black box warnings now. But we knew this from Zyprexa just look at the summary basis of approval. It was only after Lilly pushed it off-label for years that FDA finally did something.
Asenapine. Avoided studying in the elderly but just place it on the tongue It's so easly) and voila no more grandma. That of course can be explained away as a class effect or inapproriate administration (not for dementia or not sublingual).
CVAs - strokes, TIAs might be due to those pesky effects on serotonin or also possibly narrowing of arteries and veins now wasn't SP looking at intimal media thickness.
Probably won't be pickup up as anything unusual.
NMS - nasty. Your body cooks itself. Interesting how this appears related to effects on mitochondrial as is effects on diabietes, lipids, etc.. Hard to tease out and hard to tell which drug it's worse with. Oh Well just label and hope asenapine just like we do with the others.
TD - long term may be 25% with OD of older antipsychotics like haldol less with appropriate dosing. May be 10-15% with newere atypicals. This this due to better dosing or different receptor profiling. Doesn't matter may be better but this is largley not life threatening.
Phen-Fen like cardiovascular toxicity. NOT MENTIONED.
HEPATOTOXICITY - Dose and time dependent NOT MENTIONED.
BIRTH DEFECTS - NOT MENTIONED.
Other lessor effect not mentioned.
It's the comparisons and risks in certain populations with the not mentioned I'm really interested in. If they mention a couple of nasty things you've got to wonder why they're so afraid to mention other nasty AEs.
Salmon
As for tracking the subjects in tha state run institutions I'm really more afraid for all the kids, young women, etc.. who will be dosed at home for things like ADHD and post partum depression
Thanks for your insights, Salmon, they are always welcome -- and educational!
Does it matter at all that FDA only approved Saphris for "acute episodes" today?
I mean, shouldn't/wouldn't a doctor want/need to document an acute outburst to feed this to a kid?
If for no other reason, than just to protect him/herself, as going to a kid that young -- at home -- would seem to plainly be off-label, right?
The doctor is free to do it -- but will be strictly liable for ANY, and I mean ANY -- outcome, off-label.
Namaste
Or, am I missing something here? -- as I often am.
Namaste
While you are correct. That the prescriber would be liable, in reality it almost never comes to pass. Children and the elderly are currently being dosed for things like irritability with other antipsychotics, in fact I recently read where 76% of Seroquel's usage is off-label and a similar percent of physcians don't know what the approved indications and off-label indications are.
As for medical records. If you've ever seen the typical psych patient record it's more like patient better or patient worse. Or had interview - tentative dx BP-1. Whereas or even claiming ADHD with irritability is is bipolar without grandiosity which some (especially industry sponsored KOL's are pushing) may really just be an added social situation at home (Dad lost his job), or symptoms that will more likely develop into depression and anxiety disorder as an adult.
Also patients don't question their doctor's, and as we say doctors bury their mistakes. Then even if this is really mild BP which is often questionable (patients often go through multiple diagnoses as patients experience more symptoms over time and as children become more self aware and verbal) it's not likely that the drugs even work for milder forms or the risk benefits are worth it.
Then there's the likelihood that it's most likely to occur in patients who have underlying problems with a particular organ so that it will be attributed to that and the waters will be muddied, the slow addition of things to labeling as more and more things eventually come out in the literature. Just enough to build a legal defense but not really warn. Preemption (thank god it didn't go through). Tort reform and many states limiting medical malpractice so that you can only get $250 K and since it costs >$100K on average to bring a case the lawyer who gets 40% on contingency actually looses money when you figure in the costs of bringing the cases they didn't win. Also the lack of being able to get anything for lost wages in the elderly or in children in some of these states with tort reform. The difficulty of finding someone to take the initial cases, the small likelihood of winning.
Plus physicians don't even realize the risks, look at suicidality/suicides and antidepressants in kids (it may be 10% drugs.) There are several reasons for this lack of awareness. For CV effects when do you ever see a psychiatrist use a stethoscope (most likely it's at the bottom of a drawer somewhere). Plus if it's a suicide it's likely attributed to the drug. Plus psychiatrists who aren't also neurologists tend to be those med school students who focused on psych in rotations, did 1 year of general internship and then did psych. Lastly if you see 500 patients per year and even 20% are bipolar and you use 5 different drugs what's the statistical likelihood that you will see something that occurs in 1 in 500 people or if you do are you going to put 2 and 2 together.
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